HIV drug therapy duration; a Swedish real world nationwide cohort study on InfCareHIV 2009-2014.

BACKGROUND: As HIV infection needs a lifelong treatment, studying drug therapy duration and factors influencing treatment durability is crucial. The Swedish database InfCareHIV includes high quality data from more than 99% of all patients diagnosed with HIV infection in Sweden and provides a unique opportunity to examine outcomes in a nationwide real world cohort. METHODS: Adult patients who started a new therapy defined as a new 3rd agent (all antiretrovirals that are not N[t]RTIs) 2009-2014 with more than 100 observations in treatment-naive or treatment-experienced patients were included. Dolutegravir was excluded due to short follow up period. Multivariate Cox proportional hazards models were used to estimate hazard ratios for treatment discontinuation. RESULTS: In treatment-naïve 2541 patients started 2583 episodes of treatments with a 3rd agent. Efavirenz was most commonly used (n = 1096) followed by darunavir (n = 504), atazanavir (n = 386), lopinavir (n = 292), rilpivirine (n = 156) and raltegravir (n = 149). In comparison with efavirenz, patients on rilpivirine were least likely to discontinue treatment (adjusted HR 0.33; 95% CI 0.20-0.54, p<0.001), while patients on lopinavir were most likely to discontinue treatment (adjusted HR 2.80; 95% CI 2.30-3.40, p<0.001). Also raltegravir was associated with early treatment discontinuation (adjusted HR 1.47; 95% CI 1.12-1.92, p = 0.005). The adjusted HR for atazanavir and darunavir were not significantly different from efavirenz. In treatment-experienced 2991 patients started 4552 episodes of treatments with a 3rd agent. Darunavir was most commonly used (n = 1285), followed by atazanavir (n = 806), efavirenz (n = 694), raltegravir (n = 622), rilpivirine (n = 592), lopinavir (n = 291) and etravirine (n = 262). Compared to darunavir all other drugs except for rilpivirine (HR 0.66; 95% CI 0.52-0.83, p<0.001) had higher risk for discontinuation in the multivariate adjusted analyses; atazanavir (HR 1.71; 95% CI 1.48-1.97, p<0.001), efavirenz (HR 1.86; 95% CI 1.59-2.17, p<0.001), raltegravir (HR 1.35; 95% CI 1.15-1.58, p<0.001), lopinavir (HR 3.58; 95% CI 3.02-4.25, p<0.001) and etravirine (HR 1.61; 95% CI 1.31-1.98, p<0.001).Besides the 3rd agent chosen also certain baseline characteristics of patients were independently associated with differences in treatment duration. In naive patients, presence of an AIDS-defining diagnosis and the use of other backbone than TDF/FTC or ABC/3TC increased the risk for early treatment discontinuation. In treatment-experienced patients, detectable plasma viral load at the time of switch or being highly treatment experienced increased the risk for early treatment discontinuation. CONCLUSIONS: Treatment durability is dependent on several factors among others patient characteristics and ART guidelines. The choice of 3rd agent has a strong impact and significant differences between different drugs on treatment duration exist.

Medical resource utilization and cost of HIV-related care in the highly active antiretroviral therapy era at a University Clinic in Sweden.

INTRODUCTION: Little is known regarding healthcare costs for HIV/AIDS patients in the era of highly active antiretroviral therapy (HAART) and subgroups of patients according to the severity and progression of HIV infection in Sweden. The objective of this study is therefore to describe the direct medical resource use and cost of healthcare for HIV patients at a university clinic in Sweden. METHODS: A patient registry database for HIV treatment at the Department of Infectious Diseases, Sahlgrenska University Hospital, between 2000 and 2005 provided information on patient characteristics, antiretroviral drugs and dosages, tests and diagnostic procedures, outpatient visits and inpatient stays. The review used publicly available unit costs with a county council perspective, expressed in 2006 Euros. RESULTS: Two hundred and eighty-five patients with a mean age of 38 years in 2000 (64% men) were followed for 1368 patient-years. They had a mean (median) of 6.3 (0) inpatient days, 4.1 (3.7) physician visits, 4.2 (3.8) nurse visits, 2.6 (0.7) counsellor visits and 11.5 (7.7) tests and diagnostic procedures per patient-year. Only 12 deaths were recorded during the study period, and the proportion of treated patients with successful treatment (HIV-RNA < 50 copies/mL) increased from 74% to 92% during the period. The mean cost per patient-month amounted to €1069. The main cost driver was HIV drugs (51%), followed by inpatient stays (including hospitalizations for opportunistic infections; 22%), outpatient physician, nurse or therapist visits (19%) and diagnostics and tests (7%). All non-drug costs increased with a decreasing CD4 cell count. CONCLUSIONS: Overall, approximately half of the direct costs of HIV treatment were not related to antiretroviral treatment. The non-antiretroviral costs were inversely correlated with HIV-induced immune deficiency.

Predictors of virological outcome and safety in primary HIV type 1-infected patients initiating quadruple antiretroviral therapy: QUEST GW PROB3005.

BACKGROUND: Initiation of antiretroviral therapy during primary human immunodeficiency virus (HIV)-1 infection may confer long-term benefit. METHODS: After initiation of zidovudine, lamivudine, abacavir, and amprenavir therapy in patients in the QUEST cohort, predictors of virological outcome, virological and immunological changes, and adverse events were evaluated over 48 weeks. RESULTS: One hundred forty-eight patients started antiretroviral therapy during primary HIV-1 infection with < or =3 bands on Western Blot (median plasma HIV-1 RNA load, 5.4 log copies/mL; median CD4 cell count, 517 cells/mm(3)). By week 48, 36% of patients had stopped treatment or were lost to follow-up. Among the 115 patients receiving follow-up care at week 48 (102 of whom were receiving antiretroviral therapy), the median viral load decrease was -5.4 log copies/mL (interquartile range [IQR], -6.4 to -3.9 log copies/mL), and the median increase in CD4 cell count was 147 cells/mm(3) (IQR, -1 to 283 cells/mm(3)); 84.2% of patients had a viral load < or =50 copies/mL, and 44.7% of patients had a viral load < or =3 copies/mL. The median cell-associated RNA level decreased from 3.4 log copies/million PBMCs (IQR, 2.9-4.1 log copies/million PBMCs) to 0.8 log copies/million PBMCs (IQR, 0.5-1.4 log copies/million PBMCs), and the median cell-associated DNA level decreased from 2.8 log copies/million PBMCs (IQR, 2.4-3.0 log copies/million PBMCs) to 1.6 log copies/million PBMCs (IQR, 1.2-1.9 log copies/million PBMCs); 33.3% of patients had an undetectable RNA level, and 9.5% of patients had an undetectable cell-associated DNA level. The median CD8(+)/CD38(++) T cell count decreased from 459 cells/mm(3) (IQR, 208-974 cells/mm(3)) to 33 cells/mm(3) (IQR, 19-75 cells/mm(3)). Baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were independent inverse predictors for reaching a viral load < or =3 copies/mL. Eighty-three patients experienced a serious adverse event (median duration of an adverse event, 15 days).Conclusions. Initiation of antiretroviral therapy during primary HIV-1 infection was associated with very significant antiretroviral activity and a decrease in immune activation. Lower baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were predictive of achieving a viral load < or =3 copies/mL.

Differences in adherence and motivation to HIV therapy--two independent assessments in 1998 and 2002.

OBJECTIVE: The aim of this study was to compare the level of adherence and motivation in two independent cross-sectional samples of HIV-infected patients conducted in 1998 and 2002, and to investigate the relationship between adherence and motivation. METHOD: Consecutive HIV-infected patients on treatment at a Swedish clinic were asked to complete an anonymous questionnaire. In 1998, 60 patients participated and in 2002, 53 participated. In 2002, the 9-item Morisky Medication Adherence Scale (MMAS) was added to the questionnaire set. MAIN OUTCOME MEASURE: Self-reported adherence and motivation. RESULTS: In 1998, 28.1% of the respondents were considered adherent, while the corresponding proportion was 57.4% in 2002 (P = 0.002). The mean summary score for MMAS was 10.7 in 2002 (13 = perfect adherence). The proportion considered motivated were 22.4% in the 1998 survey and 41.3% in 2002 (P = 0.038). Of the respondents considered motivated in the 2002 survey, 46.7% scored the maximum summary score on the MMAS, while 8.7% of the non-motivated respondents did so (P = 0.016). CONCLUSION: The respondents in 2002 were more adherent and motivated than the respondents in 1998 and a relationship between motivation and adherence was found. The difference in adherence and motivation might be due to a new treatment model at the clinic.

Antiretroviral treatment of HIV infection: Swedish recommendations 2005.

On 2 earlier occasions, in 2002 and 2003, the Swedish Medical Products Agency (MPA) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly publicized recommendations for the treatment of HIV infection. A working group from the same expert team that produced the 2002 report has now revised the text again. Since the publication of the last treatment recommendations, 4 new medicines have become available: emtricitabine, atazanavir, fosamprenavir, and enfuvirtid. The last-mentioned belongs to a new class of HIV medications called fusion inhibitors (Box 1). It is likely that tipranavir will also be on the market soon. Simultaneously, the drug zalcitabin has been deregistered. The following updated recommendations parallel the earlier ones, but increased knowledge allows us to be more specific in our recommendations. Thus, it is now suggested that the initial treatment for HIV infection consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI); or 2 NRTIs and 1 protease inhibitor (PI). In the group of the NRTIs, stavudine is no longer recommended for this purpose. In the NNRTI group, efavirenz should be preferred to nevirapine, except under special circumstances. Finally, PIs ought to be boosted with ritonavir (PI/r). Also new are recommendations regarding treatment choices for patients co-infected with hepatitis B virus (HBV) or tuberculosis (TB). As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels), and have been supplemented with references to newly-added sections and data not referred to in earlier background documentation.

The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients.

Inadequate local cell-mediated immunity appears crucial for the establishment of chronic HIV infection. Accumulation of regulatory T cells (Treg) at the site of HIV replication, the lymphoid organs, may influence the outcome of HIV infection. Our data provide the first evidence that chronic HIV infection changes Treg tissue distribution. Several molecules characteristics of Treg (FoxP3, CTLA-4, glucocorticoid-induced TNFR family-related receptor, and CD25) were expressed more in tonsils of untreated patients compared with antiretroviral-treated patients. Importantly, most FoxP3+ cells expressed CTLA-4, but not CD69. Furthermore, a direct correlation between FoxP3 levels and viral load was evident. In contrast, FoxP3 expression was decreased in circulating T cells from untreated patients, but normalized after initiation of treatment. Functional markers of Treg activity (indoleamine 2,3-dioxygenase, TGF-beta, and CD80) were markedly increased in the tonsils of untreated patients. Our data could provide a new basis for immune-based therapies that counteract in vivo Treg and thereby reinforce appropriate antiviral immunity.

Impact of HIV type 1 genetic subtype on the outcome of antiretroviral therapy.

The objective of this study was to investigate the short-term virological outcome of antiretroviral combination therapy (ART) in relation to infection with different HIV-1 genetic subtypes. Antiretroviral drug-naive patients in Sweden were prospectively enrolled and followed for 6 months when starting ART in the period from January 1998 to January 2002. Plasma-HIV-1 RNA levels, CD4 counts, and type of ART regimen were recorded. The HIV-1 subtype was determined by direct sequencing of regions of the env or pol genes. Data from 172 patients who harbored subtypes A, B, C, D, G, and CRF01_AE were analyzed (32 A, 44 B, 34 C, 18 D, 5 G, and 19 CRF01_AE). Of all patients 84% had undetectable plasma HIV-1 RNA levels after 6 months of ART. Patients infected with CRF01_AE more often had undetectable HIV-1 RNA plasma levels than patients infected with subtypes A or D. However, the possibility that this difference is due to ethnicity cannot be ruled out. Of patients of African origin, 77% had undetectable viral load after 6 months of treatment, while the corresponding figures for Caucasians and Asians were 91% and 100%, respectively. Thus, we have found an overall good short-term virological outcome after the initiation of ART in a cohort of ARV-naive patients of diverse ethnic background infected with different HIV-1 genetic subtypes. In univariate analysis ethnicity, but not genetic subtype, correlated with virological response. However, the impact of ethnicity was moderate. Patients of African origin, who had the poorest outcome, showed a 77% virological response rate.

Expansion of CD7(low) and CD7(negative) CD8 T-cell effector subsets in HIV-1 infection: correlation with antigenic load and reversion by antiretroviral treatment.

The antiviral response of CD8 T cells involves the differentiation of naive T cells into distinct types of effector and memory cells, which may be distinguished by the level of CD7 expression. We have investigated CD8 T cells in adults and children infected with HIV-1 to determine the disease relevance of cell subsets defined by CD7. CD8 T cells from patients infected with HIV-1 displayed profound down-modulation of CD7 expression as compared with healthy subjects, with expansion of both CD7(low) and CD7(negative) effector subsets. Loss of CD7(high) cells correlated directly with HIV-1 load and was particularly pronounced in patients with rapid disease progression. CD8 T cells specific for HIV-1, as well as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were predominantly found in the CD7(low) effector cell subset. Furthermore, recovery of CD4 counts on antiretroviral therapy was associated with reversion of the skewed CD7 profile in CD8 T cells. Thus, effector CD8 T-cell subsets distinguished by lowered CD7 expression expand in a manner that correlates with the magnitude of HIV-1, EBV, and CMV antigenic challenge and contract in response to successful antiretroviral treatment. The results are discussed in relation to the dual roles of CD7 as a receptor of both costimulation and cell death.

Antiretroviral treatment of human immunodeficiency virus infection: Swedish recommendations.

The Swedish guidelines (SwG) for treatment of human immunodeficiency virus (HIV) infection have several important roles. A major task involves the promotion of a uniformly high standard of care in all HIV treatment clinics in Sweden and the identification of strengths, weaknesses and relevance of recent research findings. CD4+ T-cell counts < 200 cells/microl are clear indications for the initiation of treatment, whereas high viral loads serve as an indication for increased vigilance rather than a criterion for therapy. It is recommended that the first regimen consists of 2 nucleoside reverse transcriptase inhibitors in combination with 1 protease inhibitor or 1 non-nucleoside reverse transcriptase inhibitor. The definition of treatment failure is rigorous. Treatment change should be considered if the viral load has not fallen by at least 1.5 log in 4 weeks or is undetectable within 3-4 months. Resistance testing is endorsed at primary infection, in the event of treatment failure and in pregnant women. Interaction with experts in HIV resistance testing is emphasized. Therapeutic drug monitoring is advocated. Patients with treatment failure should be handled individually and the decision on therapeutic strategy should be based on treatment history, resistance testing and other clinical facts. The SwG do not give recommendations for some important issues such as prolonged drug holidays and preferences in initial treatment regimens. More scientific data are likely to be available soon and the SwG will be refined accordingly. The present guidelines are translated from Swedish; they are published on the Medical Products Agency (MPA) and Swedish Reference Group for Antiviral Therapy (RAV) websites (www.mpa.se and www.rav.nu.se), including 7 separate papers based on a thorough literature search. A complete reference list is available on request from the MPA.